Mathematical modeling of clinical data and experiments in mouse models suggest that cancer cells disseminating from prevalent cancers, such as those of the breast and prostate, undergo an extended period of dormancy at pre-metastatic sites. Even cancers, which causes early metastatic relapse, such as pancreatic cancer, may spawn pre-metastatic cells in the circulation and seed distant organs several years before their detection and resection. Insights into the mechanisms that enable disseminated cancer cells to survive during dormancy and then outgrow into life-threatening lesions are sorely needed in order to identify novel therapeutic targets for the prevention or treatment of metastatic disease. By using a novel powerful forward genetic screening approach, we have identified genes that promote or suppress reactivation of breast cancer in the lung. Mechanistic studies on the mediators identified through our screens suggest that the metastasis-initiating cells are cancer stem cells or revert to this state upon infiltrating a target organ and that they enter into dormancy and undergo reactivation in response to niche signals, intracellular signaling pathways and transcriptional programs which are similar to those that regulate normal adult stem cells. In addition, these studies have yielded actionable therapeutic targets. In order to fuly understand the logic of metastatic dormancy and reactivation and ultimately develop a new generation of agents to be used for metastasis prevention or therapy, it is now necessary to improve the throughput of our screens, to extend our studies to other colonization sites and other cancer types, and to enrich our mechanistic studies with the spatial and temporal resolution of advanced live imaging. On the foundation provided by these studies, it will then be possible to address more fundamental questions about the origin of metastatic stem cells and the epigenetic changes that drive their reactivation and to pursue additional therapeutic targets. Our research program spans three cancer types and multiple target organs and aims to not only shed light on the biology of the most mysterious phase of metastasis but also to bring to the clinic an entire new class of therapeutics.